Brain-specific analogues of centrally acting amines

ABSTRACT

The subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are compounds of the formula ##STR1## and the non-toxic pharmaceutically acceptable salts thereof, wherein D is the residue of a centrally acting primary, secondary or tertiary amine and ##STR2## is an unsubstituted or substituted dihydropyridyl, dihydroquinolyl or dihydroisoquinolyl radical. The corresponding ionic pyridinium, quinolinium and isoquinolinium salts ##STR3## wherein X -  is the anion of a non-toxic pharmaceutically acceptable acid, are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 785,903, filedAug. 29, 1985, now U.S. Pat. No. 4,771,059, which is acontinuation-in-part of applicant's copending application Ser. No.584,800, filed Feb. 29, 1984, now abandoned.

FIELD OF THE INVENTION

The present invention relates to new derivatives of centrally actingamines in which a primary, secondary or tertiary amine function has beenreplaced with a dihydropyridine/pyridinium salt redox system. The newdihydropyridine analogues are a delivery system for the correspondingnew quaternary compounds, which are pharmacologically active in vivo andare characterized by site-specific and sustained delivery to the brain.

BACKGROUND OF THE INVENTION

The delivery of drug species to the brain is oftimes seriously limitedby transport and metabolism factors and, more specifically, by thefunctional barrier of the endothelial brain capillary wall, i.e. theblood-brain barrier or BBB. Site-specific delivery and sustaineddelivery of drugs to the brain are even more difficult.

Indeed, the barriers separating plasma from the brain and cerebrospinalfluid (CSF) are complex systems involving passive and active transportand subserve a number of important functions. The boundary betweenplasma and the central nervous system (CNS) is much less permeable thanthat between plasma and other tissue cells to a variety of water solublesubstances, such as organic electrolytes, organic acids and bases, aswell as to large molecules such as proteins. Such a barrier alsoprovides a path for clearance from the brain of the breakdown productsof cellular metabolism. The CNS and its fluids can be consideredbasically a three-compartment system: the blood or the plasma, CSF andbrain tissue. There is a diffusion-controlled exchange between CSF andthe extracellular fluid (CF) of the brain. It has also been suggestedthat the permeabilities of blood-CSF and blood-brain barriers arepractically identical with respect to drugs and other foreignsubstances. Mayer et al, J. Pharmacol. and Exp. Therap., 125, 185(1959).

The BBB is, moreover, basically the result of the fact that theendothelial cells in the brain capillaries are joined by continuous,tight intercellular junctions, such that material has to pass throughthe cells rather than between them in order to move from blood to brain.It is interesting that there are areas within the brain, such as thesubfornical body and the postremia, in which the capillary cells are notclosely linked so that they lack the characteristics of the BBB. Theyprovide the entry of small amounts of compounds which would notordinarily enter the barriers. Hoffman and Olszewzki, Neurology(Minneap.), 11, 1081 (1961).

Foreign compounds which enter organs other than the central nervoussystem with ease, may penetrate the CNS slowly or hardly at all. Anumber of theories concerning the nature of the barrier have beenproposed. The widely accepted concept describes the boundary as afat-like layer interspersed with small pores, although the BBB is not asimple, anatomically well-defined unitary physical entity. Shuttleworth,Prog. Exp. Tumor Res., 17, 279 (1972). Penetration of such a barrier mayoccur by several processes: lipid soluble substances may passivelypenetrate into the cells, while small molecules such as water and ureamay pass through the pores. In addition to these simple physicalprocesses, carrier-mediated and active transport processes govern themovement of many molecules through the BBB. Thus, it is generallyaccepted that lipid solubility, degree of ionic dissociation orprotonation and the ability of temporary combination with membraneconstituents affect delivery through the BBB. It has been shown, forexample, that in the class of barbiturates, a quantitative correlationcould be established between their ease to pass into the brain (asreflected by the different times of onset of anesthetic action) andtheir lipid/water partition coefficient. Mark et al, J. Pharmacol. andExp. Therap., 123, 79 (1957). The role of lipid solubility in drugpenetration through the BBB is also exemplified by the better absorptionof the sparingly water-soluble thiamine propyl disulfide (TPD) ascompared to the water-soluble thiamine hydrochloride (THCl). Thomson etal, Ann. Int. Med., 74, 529 (1971). Some materials such as glucose andamino acids are transported by active mechanism, characterized bysaturation, bidirectional molecular specificity, bi-directionalcompetitive inhibition and bidirectional countertransport. Fishman, Am.J. Physiol., 206, 836 (1964).

Changes in permeability of the BBB can be caused by several pathologicaland toxicological processes. Pardridge, Connor and Crawford, CRC Crit.Rev. Toxicol., 179 (1975). A general increase in the barrierpermeability, such as a nonspecific breakdown of the barrier has,however, several consequences, including cerebral edema.

It too is well documented that the BBB is relatively impermeable to theionized forms of drugs and other molecules. Drugs which are weak organicelectrolytes appear to pass from blood to CSF to reach a steady stateratio characteristic of each molecule according to its pk_(a) and theexistence of a normal pH gradient between blood and CSF. It is clearthat it is the most difficult for quaternary pyridinium or ammoniumsalts to penetrate the BBB.

And removal of substances from the brain and CSF is obviously asignificant factor in regulating drug concentrations in the CNS. Thereare several efflux processes: bulk flow via the arachnoid villi,diffusion of lipid soluble substances into brain and blood, activetransport and metabolism by adjacent meninges. Once a drug or metaboliteenters the CSF from blood or brain by simple diffusion, it may rapidlybe removed, either by nonselective bulk flow or by active transportmechanism associated with the choroid plexus or other nondefinedstructures in the CSF compartment. It is generally accepted that highlylipid-soluble drugs leave the CSF more rapidly than poorly lipid-solubleones, but the barrier to passage of compounds from CSF has onlysuperficial similarity to the blood-CSF barrier.

Drug elimination processes from the brain are significantly directlyrelated to drug accumulation in the brain. It is generally assumed thatefflux in the opposite direction involves almost the same processes asfor entry, except that the role of the bulk flow and the metabolicprocesses in the brain are not to be overlooked.

The two elimination processes studied in the earlier literature andwhich can be said to have a certain bearing on the present inventioninvolve elimination from the brain of ionic species. Thus, it is foundthat non-metabolized ionic species, such as the acetate ion, have athree times slower elimination rate from the CSF than from the blood.Freundt, Arz., Forsch., 23, 949 (1973). An even more dramatic change inthe elimination rate was found in the case of a quaternary piperidiniumsalt. The quaternary salt, formed in situ after delivery of ahaloalkylamine, which undergoes cyclization to the quaternary salt, inthe brain, as well, was found to have an at least ten times slowerelimination rate from the brain than from the rest of the body. It wasconcluded by the authors [Ross and Froden, Eur. J. Pharmacol., 13, 46(1970)] that the outflow rate of the quaternary salt corresponded to theinflow rate. Similar results were obtained for the erythrocytes: theefflux of the quaternary salt was very slow. Ross, J. Pharm. Pharmacol.,27, 322 (1975).

A dihydropyridine⃡pyridinium redox system has now been successfullyapplied to delivery to the brain of a number of drugs. Generallyspeaking, according to this system, a dihydropyridine derivative of abiologically active compound is synthesized, which derivative can enterthe CNS through the blood-brain barrier following its systemicadministration. Subsequent oxidation of the dihydropyridine species tothe corresponding pyridinium salt leads to delivery of the drug to thebrain.

Two main approaches have been used thus far for delivering drugs to thebrain using this redox system. The first approach involves derivation ofselected drugs which contain a pyridinium nucleus as an integralstructural component. This approach was first applied to delivering tothe brain N-methylpyridinium-2-carbaldoxime chloride (2-PAM), the activenucleus of which constitutes a quaternary pyridinium salt, by way of thedihydropyridine latentiated prodrug form thereof. Thus, a hydrophiliccompound (2-PAM) was made lipoidal (i.e. lipophilic) by making itsdihydropyridine form (Pro-2-PAM) to enable its penetration throughlipoidal barriers. This simple prodrug approach allowed the compound toget into the brain as well as other organs, but this manipulation didnot and could not result in any brain specificity. On the contrary, suchapproach was delimited to relatively small molecule quaternarypyridinium ring-containing drug species and did not provide the overallideal result of brainspecific, sustained release of the desired drug,with concomitant rapid elimination from the general circulation,enhanced drug efficacy and decreased toxicity. No "trapping" in thebrain of the 2-PAM formed in situ resulted, and obviously nobrain-specific, sustained delivery occurred as any consequence thereof:the 2-PAM was eliminated as fast from the brain as it was from thegeneral circulation and other organs. Compare U.S. Pat. Nos. 3,929,813and 3,962,447; Bodor et al, J. Pharm. Sci., 67, No. 5, 685 (1978). Seealso Bodor, "Novel Approaches for the Design of Membrane TransportProperties of Drugs", in Design of Biopharmaceutical Properties ThroughProdrugs and Analogs, Roche, E. B. (ed.), APhA Academy of PharmaceuticalSciences, Washington, D.C., 98-135 (1976). Subsequent extension of thisfirst approach to delivering a much larger quaternary salt, berberine,to the brain via its dihydropyridine prodrug form was, however, found toprovide site-specific sustained delivery to the brain of that anticanceragent. See Bodor et al, Science, Vol. 214, Dec. 18, 1981, pp. 1370-1372.

The second approach for delivering drugs to the brain using the redoxsystem involves the use of a pyridinium carrier chemically linked to abiologically active compound. Bodor et al, Science, Vol. 214, Dec. 18,1981, pp. 1370-1372, outlines a scheme for this specific and sustaineddelivery of drug species to the brain, as depicted in the followingScheme 1: ##STR4## According to the scheme in Science, a drug [D] iscoupled to a quaternary carrier [QC]⁺ and the [D-QC]⁺ which results isthen reduced chemically to the lipoidal dihydro form [D-DHC]. Afteradministration of [D-DHC] in vivo, it is rapidly distributed throughoutthe body, including the brain. The dihydro form [D-DHC] is then in situoxidized (rate constant, k₁) (by the NAD⃡NADH system) to the ideallyinactive original [D-QC]⁺ quaternary salt which, because of its ionic,hydrophilic character, should be rapidly eliminated from the generalcirculation of the body, while the blood-brain barrier should preventits elimination from the brain (k₃ >>k₂ ; k₃ >>k₇). Enzymatic cleavageof the [D-QC]⁺ that is "locked" in the brain effects a sustaineddelivery of the drug species [D], followed by its normal elimination(k₅), metabolism. A properly selected carrier [QC]⁺ will also be rapidlyeliminated from the brain (k.sub. 6 >>k₂). Because of the facileelimination of [D-QC]⁺ from the general circulation, only minor amountsof drug are released in the body (k₃ >>k₄); [D] will be releasedprimarily in the brain (k₄ >k₂). The overall result ideally will be abrain-specific sustained release of the target drug species.Specifically, Bodor et al worked with phenylethylamine as the drugmodel. That compound was coupled to nicotinic acid, then quaternized togive compounds of the formula ##STR5## which were subsequently reducedby sodium dithionite to the corresponding compounds of the formula##STR6## Testing of the N-methyl derivative in vivo supported thecriteria set forth in Scheme 1. Bodor et al speculated that varioustypes of drugs might possibly be delivered using the depicted oranalogous carrier systems and indicated that use of N-methylnicotinicacid esters and amides and their pyridine ring-substituted derivativeswas being studied for delivery of amino- or hydroxyl-containing drugs,including small peptides, to the brain. No other possible specificcarriers were disclosed. Other reports of this work with the redoxcarrier system have appeared in The Friday Evening Post, Aug. 14, 1981,Health Center Communications, University of Florida, Gainesville, Fl.;Chemical & Engineering News, Dec. 21, 1981, pp. 24-25; and Science News,Jan. 2, 1982, Vol. 121, No. 1, page 7. More recently, the redox carriersystem has been substantially extended in terms of possible carriers anddrugs to be delivered. See International Patent Application No.PCT/US83/00725, filed May 12, 1983 and published Nov. 24, 1983 underInternational Publication No. W083/03968. Also see Bodor et al,Pharmacology and Therapeutics, Vol. 19, No. 3, pp. 337-386 (1983).

Nevertheless, serious need also exists in this art for new, centrallyacting drugs which can be site-specifically and sustainedly delivered tothe brain, while at the same time avoiding the aforesaid noted andnotable disadvantages and drawbacks associated with penetration of theblood-brain barrier, with dihydropyridine latentiated prodrug forms ofdrug species themselves comprising a pyridinium salt active nucleus,with the necessity for introducing critically coordinated and designed,release rate-controlling substituents onto any particular drug carriermoiety, and/or with the limitation of delivery of only known drugentities.

SUMMARY AND OBJECTS OF THE INVENTION

Accordingly, a major object of the present invention is the provision ofa new approach for delivering drugs to the brain using the redox system.This approach provides new derivatives of centrally acting amines inwhich a primary, secondary or tertiary amine function has been replacedwith a dihydropyridine/pyridinium salt redox system. The newdihydropyridine analogues of the invention are characterized by thestructual formula ##STR7## Wherein D is the residue of a centrallyacting primary, secondary or tertiary amine, and ##STR8## is a radicalof the formula ##STR9## wherein the dotted line in formula (a) indicatesthe presence of a double bond in either the 4 or 5 position of thedihydropyridine ring; the dotted line in formula (b) indicates thepresence of a double bond in either the 2 or 3 position of thedihydroquinoline ring system; m is zero or one; n is zero, one or two; pis zero, one or two, provided that when p is one or two, each R informula (b) can be located on either of the two fused rings; q is zero,one, or two, provided that when q is one or two, each R in formula (c)can be located on either of the two fused rings; and each R isindependently selected from the group consisting of halo, C₁ -C₇ alkyl,C₁ -C₇ alkoxy, C₂ -C₈ alkoxycarbonyl, C₂ -C₈ alkanoyloxy, C₁ -C₇haloalkyl, C₁ -C₇ alkylthio, C₁ -C₇ alkylsulfinyl, C₁ -C₇ alkylsulfonyl,--CH═NOR' " wherein R'" is H or C₁ -C₇ alkyl, and --CONR'R" wherein R'and R", which can be the same or different, are each H or C₁ -C₇ alkyl.Preferably, n, m, p or q is one and R is located in the 3 position ofthe dihydropyridine ring, in the 3 position of the dihydroquinoline ringsystem or in the 4 position of the dihydroisoquinoline ring system. Mostpreferably, R is --CONH₂.

The nontoxic pharmaceutically acceptable salts of the compounds offormula (I) are also within the ambit of this invention.

The new dihydropyridine analogues of formula (I) act as a deliverysystem for the corresponding quaternary compounds in vivo; thequaternary derivatives, which also are chemical intermediates to thedihydro compounds, are pharmacologically active and are characterized bysite-specific and sustained delivery to the brain when administered viathe corresponding dihydropyridine form. The new quaternary salts arecharacterized by the structural formula ##STR10## wherein D is definedas with formula (I), X⁻ is the anion of a non-toxic pharmaceuticallyacceptable acid and ##STR11## is a radical of the formula ##STR12##wherein n, p, q and R are defined as with formula (I).

Briefly then, the present invention features a dihydropyridine⃡pyridiniumsalt redox system for the specific and sustained delivery of a centrallyacting drug to the brain according to the following Scheme 2: ##STR13##

Scheme 2 shows the expected sequence of events following administrationof a compound of formula (I). Due to its lipophilic nature, thedihydropyridine compound of formula (I) will distribute throughout thebody and has easy access to the brain through the blood-brain barrier.Upon oxidation, which occurs throughout the body, the formula (I)compound will be converted to the corresponding quaternary of formula(II). The quaternary form will be "locked" preferentially in the brain,since it can be excreted easily peripherally, but cannot move readilythrough the BBB. Sustained levels of the formula (II) quaternary will bepresent at the site of action, the brain, resulting in longer durationof action.

DETAILED DESCRIPTION OF THE INVENTION

More particularly in accord with the present invention, the followingdefinitions are applicable:

The term "lipoidal" as used herein is intended to mean lipid-soluble orlipophilic.

The term "halo" encompasses fluoro, chloro, bromo and iodo.

The term "C₁ -C₇ alkyl" includes straight and branched lower alkylradicals having up to seven carbon atoms. When R, R', R", and/or R'" areC₁ -C₇ alkyl, they are preferably methyl or ethyl.

The term "C₁ -C₇ alkoxy" includes straight and branched chain loweralkoxy radicals having up to seven carbon atoms. When R is C₁ -C₇alkoxy, it is preferably methoxy or ethoxy.

The term "C₂ -C₈ alkoxycarbonyl" designates straight and branched chainradicals of the formula ##STR14## wherein the C₁ -C₇ alkyl group isdefined as above. When R is alkoxycarbonyl, it is preferablyethoxycarbonyl or isopropoxycarbonyl.

The term "C₂ -C₈ alkanoyloxy" designates straight and branched chainradicals of the formula ##STR15## wherein the C₁ -C₇ alkyl group isdefined as above. When R is alkanoyloxy it is preferably acetoxy,pivalyloxy or isobutryloxy.

The term "C₁ -C₇ haloalkyl" designates straight and branched chain loweralkyl radicals having up to seven carbon atoms and bearing one or morehalo substituents (F, Cl, Br or I), which can be the same or different.Preferably, when R is haloalkyl, the group contains 1 or 2 carbon atomsand bears 1 to 3 halogen substituents, e.g. chloromethyl ortrifluoromethyl.

The term "C₁ -C₇ alkylthio" includes straight and branched chainradicals of the type

    (C.sub.1 -C.sub.7 alkyl)--S--

wherein C₁ -C₇ alkyl is defined as before. When R is alkylthio, it ispreferably methylthio.

The terms "C₁ -C₇ alkylsulfinyl" and "C₁ -C₇ alkylsulfonyl" designateradicals of the formulas

    (C.sub.1 -C.sub.7 alkyl)--SO--

    and

    (C.sub.1 -C.sub.7 alkyl)--SO.sub.2 --,

respectively, wherein C₁ -C₇ alkyl is defined as before. When R isalkylsulfinyl or alkylsulfonyl, methylsulfinyl and methylsulfonyl arepreferred.

When R is --CH═NOR'", it is preferably --CH═NOH

When R is --CONR'R", it is preferably --CONH₂ or --CON(CH₃)₂.

The expression "hydroxyl protective group" as used hereinbelow isintended to designate a group which is inserted in place of the hydrogenatom(s) of an OH group or groups in order to prevent prematuremetabolism of said OH group or groups prior to the compound's reachingthe desired site in the body. Typical hydroxyl protective groupscontemplated by the present invention are acyl groups and carbonates.

When the hydroxyl protective group is acyl (i.e., when it is an organicradical derived from a carboxylic acid by removal of the hydroxylgroup), it preferably represents an acyl radical selected from the groupconsisting of alkanoyl having 2 to 8 carbon atoms; alkenoyl having oneor two double bonds and 3 to 8 carbon atoms; ##STR16## wherein thecycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two orthree; phenoxyacetyl; pyridinecarbonyl; and ##STR17## wherein r is zero,one, two or three and phenyl is unsubstituted or is substituted by 1 to3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbonatoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms oralkanoylamino having 2 to 6 carbon atoms.

When the acyl group is alkanoyl, there are included both unbranched andbranched alkanoyl, for example, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, 2-methylbutanoyl, pivalyl (pivaloyl),3-methylpentanoyl, 3,3-dimethylbutanoyl, 2,2-dimethylpentanoyl and thelike. Pivalyl, isobutyryl and isovaleryl are especially preferred.

When the acyl group is alkenoyl, there are included, for example,crotonyl, 2,5-hexadienoyl and 3,6-octadienoyl.

When the acyl group is ##STR18## there are included cycloalkanecarbonyland cycloalkanealkanoyl groups wherein the cycloalkane portion canoptionally bear 1 or 2 alkyl groups as substituents, e.g.cyclopropanecarbonyl, 1-methylcyclopropanecarbonyl, cyclopropaneacetyl,α-methylcyclopropaneacetyl, 1-methylcylopropaneacetyl,cyclopropanepropionyl, α-methylcyclopropanepropionyl,2-isobutylcyclopropanepropionyl, cyclobutanecarbonyl,3,3-dimethylcyclobutanecarbonyl, cyclobutaneacetyl,2,2-dimethyl-3-ethylcyclobutaneacetyl, cyclopentanecarbonyl,cyclohexaneacetyl, cyclohexanecarbonyl, cycloheptanecarbonyl andcycloheptanepropionyl. Cyclohexanecarbonyl is especially preferred.

When the acyl group is pyridinecarbonyl, there are included picolinoyl(2-pyridinecarbonyl), nicotinoyl (3-pyridinecarbonyl) and isonicotinoyl(4-pyridinecarbonyl).

When the acyl group is ##STR19## there are included, for example,benzoyl, phenylacetyl, α-phenylpropionyl, β-phenylpropionyl, p-toluyl,m-toluyl, o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl,3,4-dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6-trimethylbenzoyl,m-methylphenylacetyl, p-isobutylphenylacetyl,β-(p-ethylphenyl)propionyl, p-anisoyl, m-anisoyl, o-anisoyl,m-isopropoxybenzoyl, p-methoxyphenylacetyl, m-isobutoxyphenylacetyl,m-diethylaminobenzoyl, 3-methoxy-4-ethoxybenzoyl,3,4,5-trimethoxybenzoyl, p-dibutylaminobenzoyl,3,4-diethoxyphenylacetyl, β-(3,4,5-trimethoxyphenyl)propionyl,o-iodobenzoyl, m-bromobenzoyl, p-chlorobenzoyl, p-fluorobenzoyl,2-bromo-4-chlorobenzoyl, 2,4,6-trichlorobenzoyl, p-chlorophenylacetyl,α-(m-bromophenyl)propionyl, p-trifluoromethylbenzoyl,2,4-di(trifluoromethyl)-benzoyl, m-trifluoromethylphenylacetyl,β-(3-methyl-4-chlorophenyl)propionyl, p-dimethylaminobenzoyl,p-(N-methyl-N-ethylamino)benzoyl, o-acetamidobenzoyl,m-propionamidobenzoyl, 3-chloro-4-acetamidophenylacetyl,p-n-butoxybenzoyl, 2,4,6-triethoxybenzoyl,β-(p-trifluoromethylphenyl)propionyl, 2-methyl-4-methoxybenzoyl,p-acetamidophenylpropionyl, and 3-chloro-4-ethoxybenzoyl.

When the hydroxyl protective group is a carbonate grouping, it has thestructural formula ##STR20## i.e., it is an organic radical which can beconsidered to be derived from a carbonic acid by removal of the hydroxylgroup from the COOH portion. Y' preferably represents alkyl having 1 to7 carbon atoms; alkenyl having one or two double bonds and 2 to 7 carbonatoms;

    cycloalkyl-C.sub.r H.sub.2r -

wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero,one, two or three; phenoxy; 2-, 3-, or 4-pyridyl; or

    phenyl-C.sub.r H.sub.2r -

wherein r is zero, one, two or three and phenyl is unsubstituted or issubstituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxyhaving 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms. Mostpreferably, Y' is C₁ -C₇ alkyl, particularly ethyl or isopropyl.

Similarly, the expression "carboxyl protective group" as usedhereinbelow is intended to designate a group which is inserted in placeof the hydrogen atom(s) of a COOH group or groups in order to preventpremature metabolism of said COOH group or groups prior to thecompound's reaching the desire site in the body. Typical carboxylprotective groups are the groups encompassed by Y' above, especially C₁-C₇ alkyl, particularly ethyl, isopropyl and t-butyl. While such simplealkyl esters and the like are often useful, other carboxyl protectinggroups may be selected in order to achieve greater control over the rateof in vivo hydrolysis of the ester back to the acid and thus enhancedrug delivery. To that end, carboxyl protecting groups such as thefollowing may be used to replace the hydrogen of the --COOH group:##STR21## wherein alk is C₁ -C₆ straight or branched alkylene and thealkyl radical is straight or branched and contains 1 to 7 carbon atoms(e.g. ##STR22##

By "centrally acting primary, secondary or tertiary amine" as usedherein there is intended any drug species or the like which contains aprimary amino, secondary amino or tertiary amino function, a significant(usually, principal) pharmacological activity of which is CNS and aresult of direct action in the brain. The term "drug" as used hereinmeans any substance intended for use in the diagnosis, cure, mitigation,treatment or prevention of disease or in the enhancement of desirablephysical or mental development and conditions in man or animal.

Exemplary such centrally acting primary amines are sympatheticstimulants and related nervous system agents, e.g., phenylethylamine (astimulant), dopamine (a neurotransmitter and dopaminergic agent used,e.g., in the treatment of Parkinsonism or hyperprolactinemia), tyramine(a stimulant), L-DOPA (a dopamine precursor used, for example, in thetreatment of Parkinsonism); narcotic analgesics; other stimulants; smallpeptides, such as the di-, tri-, tetra- and pentapeptides, and othersmall 2-20 amino acid unit containing peptides, e.g., the enkephalins(for example, Tyr-Gly-Gly-Phe-Leu), which, besides being analgesics,initiate epileptic activity in the brain at doses that are about tenfoldlower than for effecting analgesic activity; larger peptides, such aspituitary hormones and related agents; growth-promoting substances;amphetamine-like drugs; anticancer and anti-Parkinsonism agents;antihypertensives; agents to enhance learning capacity and the memoryprocesses, including treatment of dementias, such as Alzheimer'sdisease; antibacterials; monoamine oxidase (MAO) inhibitor drugs; CNS orbrain important/essential amino acids, such as tryptophan (which is anantidepressant as well as a nutrient); and any like centrally actingprimary amines.

Other illustrative ultimate species of centrally active drug entitiescontaining a primary amino group and the classes of drugs of which theyare representative are as follows: amphetamine, dextroamphetamine,levamphetamine, aletamine, cypenamine and phentermine, which aresympathomimetic amines/cerebral stimulants and appetite suppressants;etryptamine, a cerebral stimulant; anileridine, which is a narcoticanalgesic; methyldopa, which is a sympatholytic agent used, e.g., inhypertension; tranylcypromine, a sympathomimetic cerebral stimulant/MAOinhibitor and antidepressant; norepinephrine, a sympatheticstimulant/adrenergic agent; hydralazine, a hypotensive; amoxicillin andampicillin, which are penicillin-type antibiotics; guanethidine, ahypotensive/sympatholytic; GABA, γ-vinyl GABA and γ-acetylenic GABA,neurotransmitters for possible use in epilepsy; doxorubicin anddaunamycin, anticancer/antitumor agents; cephalexin, a cephalosporinantibiotic; ACTH (corticotropin); LH-RH, a neurotransmitter; melphalan,a nitrogen mustard-type anticancer/antitumor agent; DON, an anticancerurea derivative; nimustine, an anticancer/antitumor nitrosoureaderivative; amiphenazole, a stimulant; debrisoquin, a hypotensive;bacampicillin and pivampicillin, which are penicillin-type antibiotics;ceforanide and cefroxadine, which are cephalosporin-type antibiotics;and6[[(hydroxyimino)phenyl]methyl]-1-[(methylethyl)sulfonyl]-1H-benzimidazol-2-amine,an antiviral agent.

Exemplary centrally acting secondary amines in accord with thisinvention and the classes of drugs of which they are representative areas follows: mitoxantrone, an anticancer/antitumor agent; epinephrine, anadrenergic agent; phenylephrine, a sympathomimetic amine/decongestant;noracymethadol, a narcotic analgesic of the methadone-type; piminodine,a narcotic analgesic of the meperidine-type; tracazolate, asedative/hypnotic; tiletamine, an anticonvulsant; propranolol,metoprolol, nadolol, timolol and atenolol, which are β-blockers;prizidilol, a centrally acting hypotensive; benzoctamine, asedative/muscle relaxant which structurally is an analogue of thephenothiazine tranquilizers; chlordiazepoxide, a tranquilizer of thebenzodiazepine-type; methamphetamine, fencamfamin, fenozolone andzylofuramine, which are sympathomimetic amines/cerebral stimulants;desipramine, nortriptyline, octriptyline, protriptyline and maprotiline,which are cerebral stimulants/tricyclic antidepressants of thedibenzazepine-type; amedalin, bupropion, cartazolate, daledalin,difluanine, fluoxetine and nisoxetine, which also are cerebralstimulants; bethanidine, a hypotensive; and ephedrine andpseudoephedrine, which are sympathomimetic amines.

Exemplary such centrally acting tertiary amines and the classes of drugsof which they are representative are as follows: methadone, levomethadylacetate, dextromoramide, propoxyphene, carbiphene and pyrroliphine,which are narcotic analgesics of the methadone-type; phenampromide andtilidine, which are narcotic analgesics of the meperidine-type;methotrimeprazine, which is a phenothiazine analgesic; clozapine andperlapine, which are sedatives/hypnotics/anticonvulsants of thebenzodiazepine-type; cloperidone, a sedative/hypnotic of thequinazolone-type; atolide, an anticonvulsant; guanethidine, asympatholytic hypotensive; chlorpromazine, propiomazine, perphenazine,trifluoperazine, promazine, triflupromazine, acepromazine,acetophenazine, butaperazine, carphenazine, fluphenazine,prochlorperazine, thiopropazate, piperacetazine and pipotiazinepalmitate, which are tranquilizers/antipsychotics of thephenothiazine-type, a number of which are also useful as sedatives (e.g.chlorpromazine, propiomazine, perphenazine and trifluoperazine);chlorprothixine, a thioxanthine calming agent which structurally is ananalogue of the phenothiazine tranquilizers; thiothixine, a thioxanthinealerting agent (used, e.g., in chronic withdrawn schizophrenia) whichstructurally is an analogue of the phenothiazine tranquilizers; doxepinand cidoxepin, tricyclic antidepressants which structurally aredibenzoxapine analogues of the phenothiazine tranquilizers; loxapine, atranquilizer/antipsychotic (used, e.g., in treating chronic and acuteschizophrenia) which structurally is an analogue of the phenothiazinetranquilizers; clomacran, clopenthixol and clothiapine, which areantipsychotics which structurally are analogues of the phenothiazinetranquilizers; clozapine, dimeprozan, perlapine and pinoxepin, whichalso are analogues of the phenothiazine tranquilizers and are variouslyused as sedatives, hypnotics and tranquilizers; pipamperone, anantipsychotic; flurazepam, adinazolam, flumezapine and metiapine,sedatives of the benzodiazepine-type, some of which are also used ashypnotics; doxapram, a medullary stimulant; dimethazan, a xanthine-typecerebral stimulant; prolintane and thozalinone, sympathomimeticamine-type cerebral stimulants; gamfexine, a cerebral stimulant of thediphenylmethane analogue type; cyclobenzaprine, a muscle relaxant;clodazon, an antidepressant; amitriptyline, imipramine, opipramol,doxepin, cidoxepin, amoxapine, azipramine, butriptyline, clomipramine,dibenzepin, dothiepin, intriptyline, ketipramine, melitracen andtrimipramine, which are tricyclic antidepressants/cerebral stimulants ofthe dibenzazepine-type (i.e. dibenzazepines and their analogues such asdibenzoxepines), all of which can be considered as analogues of thephenothiazine tranquilizers; and cyclindole, difluamine, fantridone,flubanilate, iprindole, modaline, pirandamine, pyrovalerone, tandamine,thiazesim, trazodone and trebenzomine, which also are cerebralstimulants.

Preferred classes of centrally acting primary, secondary and tertiaryamines encompassed hereby are the central neurotransmitters, anticancerand antitumor agents, antiviral agents, memory enhancers, hypotensives,sedatives, tranquilizers, antipsychotics, narcotic analgesics andcerebral stimulants, especially preferred cerebral stimulants being thetricyclic antidepressants. Among the neurotransmitters, there can bementioned amino acids, such as GABA, GABA derivatives and otheromega-amino acids, as well as glycine, glutamic acid, tyrosine, asparticacid and other natural amino acids; catecholamines, such as dopamine andnorepinephrine; serotonin, histamine and tryptamine; and peptides suchas neurotensin, luteinizing hormone-releasing hormone (LHRH),somatostatin, enkephalins such as met⁵ -enkephalin and leu⁵ -enkephalin,endorphins such as γ-, α- and β-endorphins, and vasopressin. Syntheticand semi-synthetic analogues, e.g. analogues of LHRH in which one ormore amino acid(s) has/have been eliminated and/or replaced with one ormore different amino acid(s), and which may be agonists or antagonists,are also contemplated, e.g. the primary and secondary amine LHRHanalogues disclosed in U.S. Pat. Nos. 4,377,574, 3,917,825, 4,034,082and 4,338,305. Among the anticancer and antitumor agents, there can bementioned L-alanosine, DON, bactobolin, acivicin, melphalan, adriamycin(doxorubicin), daunomycin, mitoxantrone and nimustine. Among theantiviral agents, there can be mentioned amantadine (also of possiblevalue as an anti-Parkinsonism agent); diarylamidines such as5-amidino-2-(5-amidino-2-benzofuranyl)indole and4',6-diimidazolino-2-phenylbenzo(b)thiophen; 2-amino-oxazoles such as2-guanidino-4,5-di-n-propyloxazole and 2-guanidino-4,5-diphenyloxazole;benzimidazole analogues such as the syn and anti isomers of6[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazol-2-amine;and glycosides such as glucosamine and 6-amino-6-deoxy-D-glucose. Amongthe hypotensives, there can be mentioned methyldopa, debrisoquin,hydralazine, and guanethidine and its analogues. Among the sedatives,tranquilizers and antipsychotics, there can be mentioned the manyspecific compounds of this type already disclosed above, especially thephenothiazines and benzodiazepines and their analogues. Among thenarcotic analgesics, there can be mentioned in particular themethadone-type and meperidine-type compounds specified hereinabove.Among the cerebral stimulants, there can also be mentioned the manyspecific compounds set forth hereinabove, particularly thesympathomimetic amine-type cerebral stimulants and the tricyclicantidepressants, especially preferred tricyclics being thedibenzazepines and dibenzoxapines and their analogues.

Also illustrative of the centrally acting drug species containingprimary, secondary or tertiary amine groups contemplated by thisinvention are centrally active metabolites of centrally acting drugs.Such metabolites are typified by hydroxylated metabolites of tricyclicantidepressants, such as the E- and Z-isomers of 1-hydroxynortriptyline,2-hydroxyimipramine, 2-hydroxydesipramine and 8-hydroxychloripramine;and hydroxylated metabolites of phenothiazine tranquilizers, e.g.7-hydroxychlorpromazine. Other CNS active metabolites for use hereinwill be apparent to those skilled in the art. Typically, these CNSactive metabolites have been identified as such in the scientificliterature but have not been administered as drugs themselves. In manycases, the active metabolites are believed to be comparable in CNSactivity to their parent drugs; frequently, however, the metaboliteshave not been administered per se because they are not themselves ableto penetrate the blood-brain barrier.

As indicated hereinabove, diagnostic agents, includingradiopharmaceuticals, are encompassed by the expression "centrallyacting drug" or the like as used herein. Any diagnostic agent which canbe derivatized to afford a compound of formula (I) which will penetratethe BBB and concentrate in the brain in its quaternary form (II) and canbe detected therein is encompassed by this invention. The diagnostic maybe "cold" and be detected by X-ray (e.g. radiopaque agents) or othermeans such as mass spectrophotometry, NMR or other non-invasivetechniques (e.g. when the compound includes stable isotopes such as C13, N 15, O 18, S 33 and S 34). The diagnostic alternatively may be"hot", i.e. radiolabeled, such as with radioactive iodine (I 123, I 125,I 131) and detected/imaged by radiation detection/imaging means. Typicalradiolabeled diagnostics include diotyrosine (I 125, I 131),p-iodo-N-isopropylamphetamine (I 123), iotyrosine (I 131) andiodometaraminol (I 123), which has the structural formula ##STR23## Yetother radiolabeled diagnostics include p-iodophenethylamine andp-iodobenzylamine (labeled, e.g. with I 123 or I 125). In the case ofdiagnostics, as in the case of drugs which are for the treatment ofdisease, the "locked in" quaternary form will be the form that is imagedor otherwise detected, not the original diagnostic itself. Moreover, anyof the centrally acting drugs encompassed by this invention which areintended for the treatment or prevention of medical disorders but whichcan be radiolabeled, e.g. with a radioisotope such as iodine, or labeledwith a stable isotope, can thus be converted to a diagnostic for useherein. Put another way, any compound of formula (I) of this inventionwhich can have incorporated into its structure such a radioactive orstable isotope [either directly or through incorporation of the isotopeinto the structure of the corresponding compound of formula (II)] can beused for diagnostic purposes.

It will be apparent from the known structure of the many drug speciesexemplified above, that in many cases the selected drug will possessmore than one reactive functional group, and, in particular, that thedrug may contain hydroxyl or carboxyl or other functional groups inaddition to the amino group or groups which is/are to be replaced withthe redox system, and that these additional groups will at times benefitfrom being protected during synthesis and/or during administration. Thenature of such protection is described in more detail below. Obviously,such protected drug species are encompassed by the definition of "drug"set forth hereinabove.

By "residue of a centrally acting primary, secondary or tertiary amine"as used herein there is meant that portion of the centrally acting aminewhich would remain after removal of the respective primary, secondary ortertiary amino group therefrom, e.g., in the case of phenethylamine,which has the structural formula ##STR24## the corresponding residuewould be ##STR25## In the case of centrally acting amines which alsocontain one or more hydroxy groups and/or one or more carboxy functions,the residue thereof may contain one or more of those hydroxy and/orcarboxy functions in protected form. Thus, for example, when thecentrally acting primary amine is levodopa, which has the structuralformula ##STR26## the corresponding residue would be ##STR27## whereineach Y is hydrogen or a hydroxyl protective group as defined hereinabove(typically, acyl or carbonate) and Y' is hydrogen or a carboxylprotective group as defined hereinabove (typically, C₁ -C₇ alkyl).

It will be apparent from the foregoing that different centrally actingprimary, secondary and/or tertiary amines may have the same residue asdefined herein and as represented by D in formulas (I) and (II). Thus,for example, desipramine, which is a tricyclic antidepressant having asecondary amine function, and imipramine, which is a tricyclicantidepressant having a tertiary amine function, both have the sameresidue, i.e. ##STR28## Similarly, norepinephrine and epinephrine, whichare adrenergic agents and have a primary amino group and a secondaryamino group, respectively, share the same residue, i.e. ##STR29##wherein each Y is defined as above. As a further example, one canmention the tertiary amine phenothiazine tranquilizers/antipsychotics,acepromazine and acetophenazine, which have the structures ##STR30##respectively, and which have the same residue, i.e. ##STR31##

It will also be apparent from the foregoing that the exact structure ofthe amino function in the centrally acting amine/parent drug isimmaterial insofar as concerns the structure of the instant compounds offormulas (I) and (II), for in formulas (I) and (II) the entire aminofunction in the parent drug has been replaced with adihydropyridine/pyridinium salt redox system. Thus, virtually anycentrally acting primary amine D-NH₂, secondary amine D-NHR₁ or tertiaryamine D-NR₂ R₃ can provide the drug residue D- in the instant compounds.Without being limited to specific definitions of the R₁, R₂ and R₃groups in the secondary and tertiary amines, the following definitionsof illustrative radicals are given:

R₁ can be alkyl, preferably C₁ -C₁₀ alkyl; cycloalkyl, preferably C₃ -C₈cycloalkyl; alkenyl, preferably C₂ -C₁₀ alkenyl; cycloalkenyl,preferably C₃ -C₈ cycloalkenyl; or aryl, preferably C₆ -C₁₀ aryl,particularly phenyl. Any of the foregoing R₁ radicals can optionally besubstituted by one or more (typically 1 to 3) substituents which may bethe same or different. Possible substituents on the alkyl and alkenylradicals include C₆ -C₁₀ aryl; hydroxy; hydroxy(lower alkyl)amino;substituted C₆ -C₁₀ aryl wherein the substituent(s) is/are selected fromthe aryl substituents defined below; C₃ -C₈ cycloalkyl; substituted C₃-C₈ cycloalkyl wherein the substituent(s) is/are selected from thecycloalkyl substituents defined below; halo; lower alkoxy; loweralkylthio; lower alkylsufinyl; lower alkylsulfonyl; ##STR32## alkyl).Possible substituents on the aryl radicals include lower alkyl, halo,lower alkoxy, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lowerhaloalkyl, mono(lower alkyl)amino, di(lower alkyl)amino, mono(loweralkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and loweralkysulfonyl. Possible cycloalkyl substituents include lower alkyl; C₆-C₁₀ aryl; substituted lower alkyl wherein the substituent(s) can be anyof the alkyl substituents defined above; substituted C₆ -C₁₀ arylwherein the substituent(s) can be any of the aryl substituents definedabove; halo; lower alkoxy; lower alkylthio; lower alkylsulfinyl; loweralkylsulfonyl; ##STR33## Preferred secondary amino groups --NHR₁ arelower alkylamino [unsubstituted or substituted by hydroxy orhydroxy(lower alkyl)amino] and phenylamino. Particularly preferredsecondary amino groups include methylamino, phenylamino,tert-butylamino, isopropylamino, n-butylamino, ethylamino,2-hydroxyethylamino and 2-(2'-hydroxyethylamino)ethylamino.

R₂ and R₃, which can be the same or different, can each be any one ofthe R₁ radicals defined above, or R₂ and R₃ can be combined such that--NR₂ R₃ represents a saturated monocyclic tertiary amino group,preferably derived from a secondary amine monocycle having 5 to 7 ringatoms, optionally containing another hetero atom (--O--, --S-- or --N--)in addition to the indicated nitrogen atom, and optionally bearing oneor more (typically 1 to 3) substituents such as lower alkyl, substitutedlower alkyl, C₆ -C₁₀ aryl, substituted C₆ -C₁₀ aryl, saturatedmonocyclic tertiary amino and carbamoyl. The substituted lower alkylgroups include alkyl groups substituted by one or more (typically 1 to3) C₆ -C₁₀ arylamino, hydroxy, C₂ -C₂₀ akanoyloxy, mono(loweralkyl)carbamoyl, C₆ -C₁₀ aryl or any of the other alkyl substituentsdefined in connection with R₁ above. The substituted aryl groups includearyl groups substituted by one or more (typically 1 to 3) substituentswhich can be halo or any of the other aryl substituents defined inconnection with R₁ above. Illustrative of saturated monocyclic tertiaryamine groups encompassed by the --NR₂ R₃ term are morpholino,1-pyrrolidinyl, 4-benzyl-1-piperazinyl, perhydro-1,2,4-oxathiazin-4-yl,1- or 4-piperazinyl, 4-methyl-1-piperazinyl, piperidino,hexamethyleneimino, 4-phenylpiperidino, 2-methyl-1-pyrazolidinyl, 1- or2-pyrazolidinyl, 3-methyl-1-imidazolidinyl, 1- or 3-imidazolidinyl,4-benzylpiperidino and 4-phenyl-1-piperazinyl. Preferred tertiary aminegroups encompassed by --NR₂ R₃ include di(lower alkyl)amino; N-loweralkyl-N-benzylamino; N-lower alkyl-N-phenethylamino; piperidino;pyrrolidin-1-yl; piperazin-1-yl; morpholino; piperidino substituted inthe 4-position by hydroxy-substituted lower alkyl, C₂ -C₂₀alkanoyloxy-substituted lower alkyl, carbamoyl or piperidino; andpiperazin-1-yl substituted in the 4-position by lower alkyl, C₂ -C₂₀alkanoyloxy-substituted lower alkyl, lowermonoalkylcarbamoyl-substituted lower alkyl, hydroxy-substituted loweralkyl, phenylamino-substituted lower alkyl or halophenyl. Especiallypreferred --NR₂ R₃ groupings include dimethylamino,4-[(2'-phenylamino)ethyl]piperazin-1-yl, piperidino, pyrrolidin-1-yl, 4-(3'-chlorophenyl)piperazin-1-yl, 4-methylpiperazin-1-yl,4-(2'-hydroxyethyl)piperidino, 4-[(2'-hexadecanoyloxy)ethyl]piperidino,4-(2'-hydroxyethyl)piperazin-1-yl,4-[2'-(N-methylcarbamoyl)ethyl]piperazin-1-yl, piperazin-1-yl,(N-benzyl-N-methyl)amino, diethylamino, morpholino,(4-carbamoyl-4-piperidino)piperidino, (N-methyl-N-phenethyl)amino and4-( 2'-acetoxyethyl)piperazin-1-yl.

The expression "non-toxic pharmaceutically acceptable salts" as usedherein generally includes the nontoxic salts of compounds of formula (I)formed with nontoxic, pharmaceutically acceptable inorganic or organicacids HX. For example, the salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, fumaric, methanesulfonic,toluenesulfonic and the like. The expression "anion of a non-toxicpharmaceutically acceptable acid" as used herein, e.g. in connectionwith structure (II), is intended to include anions of such inorganic ororganic acids HX.

It too will be appreciated that the radical represented by ##STR34## informula (I) must enable the compound of formula (I) to penetrate the BBBand must also be capable of being oxidized in vivo to the correspondingquaternary structure. The ionic entity which results from such in vivooxidation is prevented from efflux from the brain, while eliminationfrom the general circulation is accelerated. In contradistinction to thedrug-carrier entities disclosed, for example, in Science, Vol 214, Dec.18, 1981, pp. 1370-1372, however, there is no readily metabolicallycleavable bond between drug and quaternary portions, and the activespecies delivered in the present case is not the original drug fromwhich the compound of formula (I) was derived, but rather is the formula(II) quaternary itself.

It will also be appreciated that a compound of formula (I) may beadministered as the free base or in the form of a non-toxicpharmaceutically acceptable salt thereof, i.e. a salt which can berepresented by the formula ##STR35## wherein D, ##STR36## and HX aredefined as before; and that, regardless of the actual form in which thecompound is administered, it will be converted in vivo to a quaternarysalt of formula (II), the anion X⁻ being present in vivo. It is notnecessary that the anion be introduced as part of the compoundadministered. Indeed, even when the compound of formula (I) is used inits salt form, the anion of the formula (II) compound is not necessarilythe same as that present in the formula (I) compound. Indeed, the exactidentity of the anionic portion of the compound of formula (II) isimmaterial to the in vivo transformation of (I) to (II).

In a presently preferred embodiment of the present invention, thecentrally acting amine of which D is the residue is dopamine and theinstant redox system is thus designed to elicit a sustained andbrain-specific dopaminergic (e.g. anti-Parkinsonism oranti-hyperprolactinemia) response in the animal to which the formula (I)derivative is administered; it is believed that this effect is achievedvia in vivo conversion of the formula (I) compound to thepharmacologically active formula (II) quaternary, which is essentially"locked in" the brain. In analogous fashion, the instant redox system I→II in which D is the residue of any other centrally acting primary,secondary or tertiary amine is designed to elicit the kind ofpharmacological response which would be obtained by delivery of theprimary, secondary or tertiary amine itself to the brain, i.e. when thecentrally acting amine/parent drug is an antitumor/anticancer agent, theinstant redox system is employed to elicit an antitumor/anticancerresponse; when the parent drug is a sympathetic stimulant, the instantredox system is used to elicit a sympathetic stimulant oramphetamine-like response; when the parent drug is GABA or a relatedcompound, the instant redox system is used to elicit anantiepileptic/anticonvulsant or analgesic response; when the parent drugis a tranquilizer, the instant system is used to elicit a tranquilizingresponse; when the parent drug is an antidepressant, the instant systemis used to elicit an antidepressant response; and so forth.

With respect to the preferred embodiment referred to above, withdopamine as the parent amine, the catechol moiety thereof in certaininstances being acylated, e.g. acetylated or pivalylated, and selecting##STR37## the following reaction scheme has been devised for preparationof the formula (I) analogues: ##STR38## An alternate reaction Scheme forpreparation of the dopamine analogues is depicted below. ##STR39##

Similar schemes can be shown for the preparation of the other compoundsof the invention. The acylation step, which introduces the hydroxylprotecting groups, is only needed when there are hydroxyl groups whichit is desired to protect. Moreover, when carbonate rather than acylprotecting groups are desired, the step of introducing the protectinggroups will involve reacting the hydroxy-containing compound with ahalocarbonate of the type Y'OCOCl or Y'OCOBr (formed by reaction of Y'OHwith COCl₂ or COBr₂), rather than with an acyl halide YCl or YBr, Y andY' being as generically defined hereinabove expect that here neither Ynor Y' can be hydrogen. Also, as shown in Schemes 3 and 4, the order ofsteps may be altered; quaternization, followed by reduction, need notalways constitute the final two steps but may be carried out earlier inthe reaction sequence. Yet other reaction schemes, reactants, solvents,reaction conditions, etc. (e.g. using an anhydride rather than an acylhalide for the acylation step, or preparing a different acyl derivative,e.g. the acetyl rather than the pivalyl derivative, or using a differentZincke reagent for the exchange reaction) will be readily apparent tothose skilled in the art. Also, insofar as concerns the quaternarycompounds, when an anion different from the one obtained is desired, theanion in the quaternary salt may be subjected to anion exchange via ananion exchange resin or, more conveniently, by use of the method ofKaminski et al, Tetrahedron, Vol. 34, pp. 2857-2859 (1978). According tothe Kaminski et al method, a methanolic solution of an HX acid willreact with a quaternary ammonium halide to produce the methyl halide andthe corresponding quaternary ·X salt. Moreover, the manner in which theultimate compound is prepared should be tailored to the presence of anyother reactive groups in the molecule. For example, when the parentamine contains one or more carboxy functions, such functions willtypically be esterified, e.g. converted to the corresponding ethylester, or otherwise suitably protected, usually prior to formation ofthe quaternary compound. Thus, a wide variety of synthetic approachescan be utilized, depending on the desired structure of the finalproduct.

The process exemplified in Scheme 3, i.e. reacting a starting materialcontaining an --NH₂ group with a Zincke reagent, can be used to derivethe instant compounds wherein D is the residue of a centrally actingprimary amine directly from the corresponding centrally acting primaryamine/parent drugs. However, if it is desired to prepare the instantcompounds wherein D is the residue of a centrally acting secondary ortertiary amine via the process shown in Scheme 3, then one will not usethe parent secondary or tertiary amine as the starting material butwould instead use the corresponding primary amine as the startingmaterial. Alternatively, a compound of the formula

    D-Hal

wherein Hal is chloro or bromo and D is the residue of a centrallyacting primary, secondary or tertiary amine can be reacted withnicotinamide or the like (as depicted in Scheme 4) to afford to desiredcompounds of the invention, regardless of whether the parent drug is aprimary, secondary or tertiary amine.

Various illustrative synthetic schemes as applied to specific compoundsof the invention are set forth below in the section entitled"Illustrative Synthetic Methods". While the sequence of reaction stepscan be varied in many cases, in general the final step (except in thecase of optional salt formation or possibly in the case ofradiolabeling) will be reduction of a quaternary compound of formula(II) to the corresponding dihydro compound of formula (I). The reductionis usually conducted at a temperature from about -10° C. to roomtemperature, for a period of time from about 10 minutes to 2 hours,conveniently at atmospheric pressure. Typically, a large excess ofreducing agent is employed, e.g., a 1:5 molar ratio of reducing agent tostarting compound of formula (II). The process is conducted in thepresence of a suitable reducing agent, preferably an alkali metaldithionite such as sodium dithionite or an alkali metal borohydride suchas sodium borohydride or lithium aluminum borohydride, in a suitablesolvent. Sodium dithionite reduction is conveniently carried out in anaqueous solution; the dihydro product of formula (I) is usuallyinsoluble in water and thus can be readily separated from the reactionmedium. In the case of sodium borohydride reduction, an organic reactionmedium is employed, e.g., a lower alkanol such as methanol, an aqueousalkanol or other protic solvent.

When a Zincke reagent is utilized in the reaction sequence, e.g. whenScheme 3 is employed, such reagent can be prepared by reacting1-chloro-2,4-dinitrobenzene with a compound of the formula ##STR40##wherein R, n, p and q are defined as with formula (I), to afford thecorresponding Zincke reagent of the formula ##STR41## respectively.Thus, for example, the specific Zincke reagent depicted in Scheme 3 canbe prepared by reacting nicotinamide with 1-chloro-2,4-dinitrobenzene.See also Zincke et al, Annalen, 1904, 333, 296; Lettre, Annalen, 1953,579, 123; Keijzer et al, Hetrocycles, Vol. 16, No. 10, 1981, 1687.

In the case of radiodiagnostics, the synthetic method of choicegenerally involves introducing the radioactive element toward the end ofthe reaction sequence, rather than using the radiolabeled parent drugitself as the starting material. Schemes 5 and 6 below are illustrativeof such instances of tailoring chemical synthesis to the particular druginvolved. Scheme 5 depicts synthesis of an analogue of I 123 labeledmetaraminol; Scheme 6 depicts a synthetic route to radioiodinatedbenzylamine and phenethylamine analogues. ##STR42##

Suitable nontoxic pharmaceutically acceptable carriers for use with thetopic compounds of formula (I), e.g., those less toxic than the targetdrug species themselves, will be apparent to those skilled in this art.Compare, for example, Remington's Pharmaceutical Sciences, 4th Edition(1970). Obviously, the choice of suitable carriers will depend upon theexact nature of the particular dosage form selected, as well as upon theidentity of the compound to be administered. The therapeutic dosagerange for administration of a compound according to this invention willgenerally be the same as, or less than, those characteristically used inthis art for administration of the known primary, secondary or tertiaryamine/parent drug of which the instant compound is an analogue.Naturally, such therapeutic dosage ranges will vary with the size of thepatient, the condition for which the compound is administered, theparticular dosage form employed, route of administration and the like.The quantity of given dosage form needed to deliver the desired dosewill of course depend upon the concentration of the compound of formula(I) in any given pharmaceutical composition/dosage form thereof.Obviously, in the case of diagnostic agents, the dosage of formula (I)compound used will be a quantity sufficient to deliver an amount ofradioisotope, stable isotope or the like which can be effectivelydetected by radioimaging or other detection means. The amount ofradioisotope, stable isotope or the like present in the dosage form willbe within or below the ranges conventionally used for diagnosticpurposes.

The ability of the topic compounds to cross the BBB and to be "lockedinto" the brain allows administration in a site-specific manner. Acombination of the present dihydropyridine ⃡ pyridinium salt redoxsystem with a sustained release system will further enhance thissite-specificity. Thus, a preferred embodiment of the inventioncomprises formulating the compound of formula (I) or its salt utilizinga sustained release carrier system and/or route of administrationcapable of slowly releasing the chemical, e.g., sustained releasetablets and capsules for oral administration; subcutaneous injection, orimplantation of drugs in solid pellet form (for example, distributed ina biodegradable polymer); intramuscular injection of the compound insolution in oil or suspended in a repository vehicle; a transdermaldelivery device or form such as an ointment to be applied locally to thedesired site (when the drug is susceptible of delivery through theskin), slow intravenous infusion and the like. The rate of release ofcompound from the sustained release system should be comparable to therate of in vivo oxidation of the dihydro form of the redox system inorder to achieve the greatest degree of enhancement of specificity.

ILLUSTRATIVE SYNTHETIC METHODS Method A

The primary amine is reacted with the Zincke reagent of the formula##STR43## in the presence of a suitable base, e.g. triethylamine, in anappropriate organic solvent, e.g. methanol, to afford the correspondingquaternary derivative of formula (II), which is then reduced bytreatment with sodium dithionite or sodium borohydride as generallydescribed hereinabove to afford the desired compound of formula (I).

The representative primary amines listed below may be derivatized inthis manner to the corresponding pyridinium and dihydropyridineanalogues of this invention.

The foregoing procedure may be repeated using a Zincke reagent of theformula ##STR44## prepared from picolinamide or isonicotinamide,respectively, to convert primary amines such as those specificallymentioned in connection with this method to the corresponding quaternaryand dihydro derivatives.

      STARTING QUATERNARY DIHYDRO MATERIAL INTERMEDIATE(CATION) DERIVATIVE      ##STR45##      ##STR46##      ##STR47##      ##STR48##      ##STR49##      ##STR50##      ##STR51##      ##STR52##      ##STR53##      ##STR54##      ##STR55##      ##STR56##      ##STR57##      ##STR58##      ##STR59##      ##STR60##      ##STR61##      ##STR62##      ##STR63##      ##STR64##      ##STR65##      ##STR66##      ##STR67##      ##STR68##      ##STR69##      ##STR70##      ##STR71##      ##STR72##      ##STR73##      ##STR74##      ##STR75##      ##STR76##      ##STR77##      ##STR78##      ##STR79##      ##STR80##      ##STR81##      ##STR82##      ##STR83##      ##STR84##      ##STR85##      ##STR86##      ##STR87##      ##STR88##      ##STR89##      ##STR90##      ##STR91##      ##STR92##      ##STR93##      ##STR94##      ##STR95##      ##STR96##      ##STR97##      ##STR98##      ##STR99##      ##STR100##      ##STR101##      ##STR102##      ##STR103##      ##STR104##      ##STR105##      ##STR106##      ##STR107##      ##STR108##      ##STR109##      ##STR110##

Method B

This is a variation of Method A used when the parent primary aminecontains a --COOH function which is to be protected.

The parent compound is first converted to the corresponding ethyl ort-butyl ester by conventional esterification techniques. That ester isthen used as the starting material in Method A and that method isrepeated.

Obviously, other esters may be similarly prepared in the first step byuse of other esterifying agents.

The representative compounds listed below may be derivatized in thismanner to the corresponding quaternary and dihydro compounds. Omegaamino acids in addition to GABA (which is shown below), other naturalamino acids such as glycine, aspartic acid and glutamic acid, and smallpeptides (2-20 amino acids, e.g. met⁵ -enkephalin and leu⁵ -enkephalin)may be similarly derivatized.

The picolinamide and isonicotinamide quaternary and dihydro derivativesof the drugs specifically mentioned for derivatizing according to thismethod may be similarly prepared, using the appropriate Zincke reagent.See Method A.

      STARTING QUATERNARY DIHYDRO MATERIAL INTERMEDIATE(CATION) DERIVATIVE      ##STR111##      ##STR112##      ##STR113##      ##STR114##      ##STR115##      ##STR116##      ##STR117##      ##STR118##      ##STR119##      ##STR120##      ##STR121##      ##STR122##      ##STR123##      ##STR124##      ##STR125##      ##STR126##      ##STR127##      ##STR128##      ##STR129##      ##STR130##      ##STR131##      ##STR132##      ##STR133##      ##STR134##      ##STR135##      ##STR136##      ##STR137##      ##STR138##      ##STR139##      ##STR140##      ##STR141##      ##STR142##      ##STR143##      ##STR144##      ##STR145##      ##STR146##      ##STR147##      ##STR148##      ##STR149##      ##STR150##      ##STR151##      ##STR152##      ##STR153##      ##STR154##      ##STR155##      ##STR156##      ##STR157##      ##STR158##      ##STR159##      ##STR160##      ##STR161##

Method C

This is a variation of Method A used when the parent primary aminecontains one or more OH functions which are to be protected.

The drug is first reacted with excess trimethylacetyl chloride, understrongly acid conditions, to convert the hydroxy group(s) to pivalyloxygroup(s). That protected derivative is then used as the startingmaterial in Method A and that method is repeated. Alternatively, thefirst two steps may be reversed, i.e., the drug may be first reactedwith the Zincke reagent to form the unprotected quaternary, which maythen be reacted with trimethylacetyl chloride to form the protectedquaternary. The protected quaternary may then be reduced to theprotected dihydro compound as in Method A.

Various other hydroxy protecting groups may be introduced in similarfashion.

The representative drugs listed below may be derivatized in this mannerto the corresponding quaternary and dihydro compounds. The correspondingpicolinamide and isonicotinamide quaternary and dihydro derivatives maybe similarly prepared, using the appropriate Zincke reagent. See MethodA.

      STARTING QUATERNARY DIHYDRO MATERIAL INTERMEDIATE(CATION) DERIVATIVE      ##STR162##      ##STR163##      ##STR164##      ##STR165##      ##STR166##      ##STR167##      ##STR168##      ##STR169##      ##STR170##      ##STR171##      ##STR172##      ##STR173##

Method D

This variation of Method A can be used when the drug contains one ormore OH and COOH functions which are to be protected. The protectinggroups, typically the ethyl or t-butyl ester and pivalyloxy groups, areintroduced as described in Methods B and C, in the sequence consideredmost convenient. The amine function is derivatized according to MethodA.

The representative drugs listed below may be derivatized in this mannerto the corresponding quaternary and dihydro compounds. The correspondingpicolinamide and isonicotinamide quaternary and dihydro derivatives maybe similarly prepared, using the appropriate Zincke reagent. See MethodA.

      STARTING QUATERNARY DIHYDRO MATERIAL INTERMEDIATE(CATION) DERIVATIVE      ##STR174##      ##STR175##      ##STR176##      ##STR177##      ##STR178##      ##STR179##      ##STR180##      ##STR181##      ##STR182##

Method E

Method A is followed, using a Zincke reagent of the formula ##STR183##prepared from 3-quinolinecarboxamide, in place of the Zincke reagentshown in Method A.

The representative starting materials listed below may be derivatized inthis manner to the corresponding quaternary and dihydro compounds, asmay the remaining drugs listed with Method A.

Similarly, Method E may be combined with Methods B, C or D to afford thecorresponding 3-quinoline-carboxamide derivatives, e.g. of the drugslisted with those methods.

The foregoing procedure may be repeated using a Zincke reagent of theformula ##STR184## deirved from 4-isoquinolinecarboxamide, in place ofthe Zincke reagent shown above, to convert drugs such as those mentionedwith Methods A, B, C, or D to the corresponding4-isoquinolinecarboxamide derivatives.

The general procedures depicted above may be utilized to provide the1,2-dihydro derivatives as well as the depicted 1,4-dihydros.

    __________________________________________________________________________    STARTING         QUATERNARY            DIHYDRO                                MATERIAL         INTERMEDIATE(CATION)  DERIVATIVE                             __________________________________________________________________________     ##STR185##                                                                                     ##STR186##                                                                                          ##STR187##                             ##STR188##                                                                                     ##STR189##                                                                                          ##STR190##                             ##STR191##                                                                                     ##STR192##                                                                                          ##STR193##                             ##STR194##                                                                                     ##STR195##                                                                                          ##STR196##                             ##STR197##                                                                                     ##STR198##                                                                                          ##STR199##                             ##STR200##                                                                                     ##STR201##                                                                                          ##STR202##                             ##STR203##                                                                                     ##STR204##                                                                                          ##STR205##                             ##STR206##                                                                                     ##STR207##                                                                                          ##STR208##                            __________________________________________________________________________     PG,78

Method F

An ether solution of a compound of formula (I) is treated with anequivalent amount of anhydrous p-toluenesulfonic acid and dissolved indry ether. Mixing at room temperature is continued until the imminiumsalt precipitates out of solution. The salt is then removed byfiltration.

Imminium salts which may be prepared in this manner include thosederived from the following compounds of the invention: ##STR209##

Method G

The compounds of formulas (I) and (II) corresponding to the secondaryamines/parent drugs listed below are prepared by selecting thecorresponding primary amines as the starting materials and followingMethod C described hereinabove. Thus, the hydroxy groups are firstprotected, the protected primary amines are then reacted with the Zinckereagent to afford the quaternary derivatives and the quaternaries arethen reduced to afford the desired compounds of formula (I).

Different protecting groups from those shown may be introduced in asimilar manner.

The picolinamide and isonicotinamide quaternary and dihydro derivativescorresponding to the depicted nicotinamide derivatives may be similarlyprepared, using the appropriate Zincke reagents, as described in MethodA.

Method E described hereinabove may be combined with Method G to affordthe corresponding 3-quinoline-carboxamide and 4-isoquinolinecarboxamidederivatives, e.g. of the parent drugs listed with this method.

      PARENT STARTING QUATERNARY DIHYDRO DRUG MATERIAL INTERMEDIATE(CATION)     DERIVATIVE      ##STR210##      ##STR211##      ##STR212##      ##STR213##      ##STR214##      ##STR215##      ##STR216##      ##STR217##

Method H

The compounds of formulas (I) and (II) corresponding to the secondaryand tertiary amines/parent drugs listed below are prepared by selectingthe corresponding compounds of the formula

    D-Hal

as the starting materials, reacting those starting materials withnicotinamide to afford the quaternary intermediates and then reducingthe quaternaries with Na₂ S₂ O₄ to afford the desired dihydroderivatives.

The foregoing procedure may be repeated using picolinamide,isonicotinamide, 3-quinolinecarboxamide or 4-quinolinecarboxamide inplace of the compounds of formulas (I) and (II) corresponding to parentdrugs such as those specifically mentioned below.

When the parent secondary and tertiary amines contain OH and/or COOHgroups in need of protection, suitable protecting groups can beintroduced before or after formation of the quaternary derivatives. See,for example, Scheme 4 and Methods B, C and D hereinabove.

Method H can also be employed to prepare the compounds of formulas (I)and (II) corresponding to the primary amines listed in Methods A throughE; see, for example, Scheme 4.

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      PARENT STARTING QUATERNARY DIHYDRO DRUG MATERIAL INTERMEDIATE(CATION)     DERIVATIVE      ##STR394##      ##STR395##      ##STR396##      ##STR397##      DIMEPROZAN      ##STR398##      ##STR399##      ##STR400##      ##STR401##      PERLAPINE      ##STR402##      ##STR403##      ##STR404##      ##STR405##      PINOXEPIN      ##STR406##      ##STR407##      ##STR408##      ##STR409##      PROLINTANE      ##STR410##      ##STR411##      ##STR412##      ##STR413##      THOZALINONE      ##STR414##      ##STR415##      ##STR416##      ##STR417##      GAMFEXINE      ##STR418##      ##STR419##      ##STR420##      ##STR421##      AMITRIPTYLINE      ##STR422##      ##STR423##      ##STR424##      ##STR425##      CYCLOBENZAPRINE      ##STR426##      ##STR427##      ##STR428##      ##STR429##      IMIPRAMINE      ##STR430##      ##STR431##      ##STR432##      ##STR433##      AMOXAPINE      ##STR434##      ##STR435##      ##STR436##      ##STR437##      AZIPRAMINE      ##STR438##      ##STR439##      ##STR440##      ##STR441##      BUTRIPTYLINE      ##STR442##      ##STR443##      ##STR444##      ##STR445##      ACETOPHENAZINE      ##STR446##      ##STR447##      ##STR448##      ##STR449##      CLOTHIXAMIDE

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In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended as illustrative and in nowise limitative.

EXAMPLE 1 Preparation of1-(3,4-Dihydroxy)phenethyl-3-carbamoylpyridinium Chloride

The Zincke reagent, 1-(2,4-dinitro)phenyl-3-carbamoylpyridinium chloride(3.56 g, 0.01 mole), in methanol (10 ml), is added over a 10 minuteperiod to a mixture of dopamine hydrobromide (2.34 g, 0.01 mole) andtriethylamine (1.4 ml, 0.01 mole) in methanol (20 ml). A deep red coloris immediately observed. The reaction mixture is stirred and heated atgentle reflux. After approximately 10 minutes, the red color begins tofade and precipitation of a yellow solid commences. Forty minutes later,the yellow product is collected by filtration. Recrystallization from amixture of methanol and ethyl ether gives a pale cream powder melting at246°-248° C. Yield 1.9 g, 73%. The product has the structural formula##STR634## as confirmed by NMR and UV.

EXAMPLE 2 Preparation of1-(3,4-Dihydroxy)phenethyl-3-carbamoyl-1,4-dihydropyridine

1-(3,4-Dihydroxy)phenethyl-3-carbamoylpyridinium chloride (430 mg, 15mmol), is added to 100 ml of an ice-cold, aqueous solution of sodiumbicarbonate (7.6 g, 90 mmol), sodium dithionite (13.75 g, 80 mmol) andethyl acetate (60 ml). Nitrogen is bubbled into the mixture throughoutthe reaction. Addition of the pyridinium chloride starting materialcauses a yellow color to develop. Stirring is continued and the reactionmixture is maintained at approximately 0° C. for about one and one-halfhours, after which time the ethyl acetate and aqueous layers areseparated and the aqueous layer is extracted four times with 50 mlportions of ethyl acetate. The combined organic layers are dried overanhydrous magnesium sulfate and evaporated to dryness under reducedpressure. The soft yellow solid (280 mg, 75%) which remains is rapidlyoxidized by methanolic silver nitrate at room temperature. Based on NMRspectra and UV and high resolution mass spectroscopy, the product isassigned the structural formula ##STR635##

EXAMPLE 3 Preparation of1-(3,4-Dipivaloyloxy)phenethyl-3-carbamoylpyridinium Trifluoroacetate

1-(3,4-Dihydroxy)phenethyl-3-carbamoylpyridinium chloride monohydrate(350 mg, 1.12 mmol) is dissolved in trifluoroacetic acid (5 ml) undernitrogen at room temperature. Pivaloyl chloride (0.3 ml, 24 mmol) isadded dropwise to the stirred solution. Stirring is continued for onehour, after which time volatile material is removed under reducedpressure, leaving an oily residue. Extensive trituration with ethylether gives a fine white powder, which is collected by filtration andwashed with additional ethyl ether. Yield 410 mg, 67%. The product isfurther characterized by the structural formula: ##STR636##

EXAMPLE 4 Preparation of1-(3,4-Dipivaloyloxy)phenethyl-3-carbamoyl-1,4-dihydropyridine

Substitution of an equivalent quantity of1-(3,4-dipivaloyloxy)phenethyl-3-carbamoylpyridinium trifluoroacetatefor the 1-(3,4-dihydroxy)phenethyl-3-carbamoylpyridinium chloride usedin Example 2 and substantial repetition of the procedure detailed inthat Example affords the desired product of the formula: ##STR637##

EXAMPLE 5 Preparation of (3,4-Dipivaloyloxy)phenethylamine Maleinate

Dopamine hydrobromide (11.7 g) is suspended in trifluoroacetic acid(117.5 ml) and pivaloyl chloride (13.65 ml) is added dropwise underargon. After one-half hour, water (0.75 ml) is added and solvent isevaporated under vacuum. The residue is dissolved in chloroform (200 ml)and washed, first with water, then with cold sodium bicarbonatesolution, then again with water. The resultant solution is dried overanhydrous sodium sulfate and evaporated under vacuum. The residual oilis dissolved in 2-propanol (25 ml) and maleic acid (5.8 g) in warm2-propanol (30 ml) is then added. Ethyl ether (100 ml) is added and themixture is refrigerated at 0° C. overnight. The product is removed byfiltration. Yield 3.8 g, m.p. 146°-8° C. The product is furthercharacterized by the structural formula: ##STR638##

EXAMPLE 6 Preparation of1-(3,4-Dipivaloyloxy)phenethyl-3-carbamoylpyridinium Chloride

Substitution of an equivalent quantity of(3,4-dipivaloyloxy)phenethylamine maleinate for the dopaminehydrobromide used in Example 1 and substantial repetition of theprocedure detailed in that Example affords the desired product of theformula: ##STR639##

EXAMPLE 7 Preparation of1-(3,4-Dipivaloyloxy)phenethyl-3-carbamoyl-1,4-dihydropyridine

Substitution of an equivalent quantity of1-(3,4-dipivaloyloxy)phenethyl-3-carbamoylpyridinium chloride for the1-(3,4-dihydroxy)phenethyl-3-carbamoylpyridinium chloride employed inExample 2 and substantial repetition of the procedure there detailedaffords the desired product of the structural formula: ##STR640##

EXAMPLE 8 Preparation of 1-(2,4-Dinitro)phenyl-3-carbamoylpyridiniumChloride

1-Chloro-2,4-dinitrobenzene (20 g) is fused with nicotinamide (8 g) on asteam bath for one hour. The homogenous dark orange glassy materialwhich results is dissolved in methanol (100 ml), with heating. Ethylether (400 ml) is added and a sticky yellow precipitate forms. The etheris removed, and the residue is washed again in the same way. Then, theresidue is dissolved in water (200 ml), with heating. Activated charcoalis added and the mixture is refluxed for 15 minutes and filtered. Ayellow glassy product, the desired Zincke reagent, forms uponevaporation of the solvent.

EXAMPLE 9 Preparation of 3-Carbamoyl-1-(3'-carboxy)propylpyridiniumChloride

The Zincke reagent prepared as in Example 8 (3.56 g, 0.01 mol) isdissolved in methanol (10 ml) and added slowly to a solution of ethyl4-aminobutyrate hydrochloride (1.67 g, 0.01 mol) in methanol (20 ml).The deep red color of the resultant solution fades to a light orangecolor with stirring. The mixture is heated to a gentle boil and allowedto reflux for 30 minutes, then is stirred overnight. Crystals ofdinitroaniline (10 g) are removed by filtration and the filtrate isevaporated to dryness. Recrystallization from a mixture of methanol andethyl ether affords an orange product, which is assigned the followingstructure on the basis of NMR spectra and elemental analysis: ##STR641##

EXAMPLE 10 Preparation of3-Carbamoyl-1-(3'-ethoxycarbonyl)propylpyridinium Chloride

The free acid product of Example 9 is suspended in ethanol. HCl gas isbubbled through the suspension at 0° C. for 45 minutes. The reactionmixture is refluxed for one hour, then allowed to cool to roomtemperature, producing a white precipitate. Removal of the precipitateand evaporation of the solvent produces a yellow oil, which is dissolvedin a minimum amount of acetonitrile, filtered and dried. Thin layerchromatography reveals the presence of one product, which is assignedthe following structure on the basis of IR, UV and NMR spectra:##STR642##

EXAMPLE 11 Preparation of3-Carbamoyl-1-(3'-ethoxycarbonyl)propyl-1,4-dihydropyridine

3-Carbamoyl-1-(3'-ethoxycarbonyl)propylpyridinium chloride (500 mg, 1.66mmol) is dissolved in cold deaerated water and maintained under nitrogenat 0° C. Sodium bicarbonate (0.84 g, 9.96 mmol) is added, followed bysodium dithionite (1.16 g, 6.64 mmol). Ethyl acetate is added and themixture is stirred at 0° C., under nitrogen, for approximately one andone-half hours. Separation of the phases and drying of the organic layeraffords 0.15 g (39% yield) of a yellow oil. The following structure isassigned to the product on the basis of UV and NMR spectra: ##STR643##

EXAMPLE 12 Preparation of3-Carbamoyl-1-(3'-ethoxycarbonyl)propylpyridinium Bromide

Nicotinamide (7.32 g, 0.06 mol) is dissolved in dimethylformamide andethyl 4-bromobutyrate (17.16 ml 0.12 mol) is added dropwise. Thereaction mixture is brought to the reflux temperature and thenmaintained at that temperature for 3 hours. The solution is then allowedto cool to room temperature and stirred for 24 hours. The solvent isevaporated and the residue is washed with ethanol, separated byfiltration and dried in a vacuum oven. Obtained in this manner is awhite powder (6.2 g), melting at 121°-123° C. and having the structure##STR644## as confirmed by elemental analysis and UV, IR and NMRspectra.

EXAMPLE 13 Preparation of3-Carbamoyl-1-(3'-ethoxycarbonyl)propyl-1,4-dihydropyridine

3-Carbamoyl-1-(3'-ethoxycarbonyl)propylpyridinium bromide (500 mg) isdissolved in 10 ml of deaerated ice cold aqueous ethanol (20%). Sodiumbicarbonate (0.80 g) is added, followed immediately by sodium dithionite(1.10 g). Ethyl acetate is then added and the resultant yellow solutionis stirred for one and one-half hours in an ice bath. Chloroform isadded and the organic layer is dried over anhydrous sodium sulfate andevaporated. The resultant yellow oil is assigned the structure##STR645## based on UV and NMR spectra and elemental analysis.

The present invention can thus be seen to provide two major classes ofnovel chemical compounds, i.e. the compounds of general formula (I)above, including their salts, and the compounds of general formula (II)above, wherein D is the residue of a centrally acting primary, secondaryor tertiary amine and the other structural variables are as definedbroadly above. Within each of these major classes, the followingsubclasses are particularly noteworthy:

(A) Compounds of formulas (I) and (II) wherein the D portion of thecompound of formula (I) or (II) is identical to the correspondingportion of the centrally acting amine from which D can be considered tobe derived. Preferred groups of compounds in this subclass include thefollowing:

(1) Cerebral stimulants, including sympathomimetic amine-type cerebralstimulants, such as amphetamine, dextroamphetamine, levamphetamine,aletamine, cypenamine, phentermine, methamphetamine, fencamfamin,fenozolone, zylofuramine, phenethylamine, prolintane, thozalinone,etryptamine and tranylcypromine; tricyclic antidepressant-type cerebralstimulants, especially dibenzazepines, dibenzoxepines and theiranalogues, e.g. desipramine, nortriptyline, protriptyline, maprotiline,octriptyline, amitriptyline, imipramine, opipramol, doxepin, cidoxepin,amoxapine, azipramine, butriptyline, clomipramine, dibenzepin,dothiepin, intriptyline, ketipramine, melitracen and trimipramine; andmany other cerebral stimulants, alerting agents and antidepressants ofvarious types, as exemplified by thiothixine, dimethazan, doxapram,gamfexine, clodazon, amedalin, bupropion, cartazolate, daledalin,cyclindole, difluanine, fantridone, flubanilate, iprindole, modaline,pirandamine, pyrovalerone, tandamine, thiazesim, amiphenazole, trazodoneand trebenzomine;

(2) Anticancer or antitumor agents, e.g. daunamycin, doxorubicin,bactobolin, mitoxantrone and nimustine and the like;

(3) Antiviral agents, e.g. amantadine,5-amidino-2-(5-amidino)-2-benzofuranyl)indole,4',6-diimidazolino-2-phenylbenzo(b)thiophene,2-guanidino-4,5-di-n-propyloxazole, 2-guanidino-4,5-diphenyloxazole,glucosamine, 6-amino-6-deoxy-D-glucose,6[[(hydroxyimino)phenyl]methyl]-1-[(methylethyl)sulfonyl]-1H-benzimidazol-2-amineand the like;

(4) Neurotransmitters, e.g. tryptamine, dopamine, tyramine,somatostatin, vasopressin, serotonin and histamine;

(5) Hypotensives, including β-adrenergic blockers, e.g. propranolol,metoprolol, nadolol, timolol and atenolol; and other hypotensives, e.g.hydralazine, guanethidine, prizidilol, bethanidine and debrisoquin;

(6) Analgesics, including phenothiazine-type analgesics such asmethotrimeprazine; and narcotic analgesics, particularly those of themeperidine-type, e.g. anileridine, tilidine, phenampromide andpiminodine, and those of the methadone-type, e.g. methadone,levomethadyl acetate, dextromoramide, propoxyphene, carbiphene,pyrroliphine and noracymethadol;

(7) Sedatives, tranquilizers, hypnotics, antipsychotics,anticonvulsants, including benzodiazepines and their analogues, used,for example, as sedatives, hypnotics, anticonvulsants, andtranquilizers, e.g. perlapine, clozapine, flurazepam, adinazolam,flumezapine, metiapine and chlordiazepoxide; thioxanthine calmingagents, e.g. chloroprothixine; muscle relaxants, e.g. cyclobenzaprine;phenothiazines and their analogues, used, for example, as tranquilizersand antipsychotics, e.g. chlorpromazine, propiomazine, perphenazine,trifluoperazine, promazine, triflupromazine, acetophenazine,butaperazine, carphenazine, fluphenazine, prochlorperazine,thiopropazate, piperacetazine, pipotiazine palmitate, acepromazine,loxapine, clomacran, clopenthixol, clothiapine, clozapine, dimeprozan,perlapine and pinoxepin; other antipsychotics, e.g. pipamperone; othersedatives and hypnotics, such as benzoctamine and tracazolate; and otheranticonvulsants, such as tiletamine and atolide;

(8) LHRH and its analogues containing a primary, secondary or tertiaryamino group;

(9) Antibiotics, e.g. bacampicillin, pivampicillin and the like; and

(10) Diagnostics, especially radiopharmaceuticals, such asradioiodinated p-iodometaraminol, radioiodinated p-iodobenzylamine,radioiodinated p-iodophenethylamine and radioiodinatedp-iodo-N-isopropylamphetamine.

Especially preferred compounds in subclass (A) are those in which D isthe residue of a compound encompassed by groups (1) and (7) above,particularly the tricyclic antidepressants.

(B) Compounds of formulas (I) and (II) wherein the centrally actingamine from which D can be considered to be derived also contains atleast one --COOH functional group, and D in formula (I) or (II)contains, in place of at least one of the --COOH functional groups insaid amine, at least one --COOY' group wherein Y' is a hydrolytically ormetabolically cleavable carboxyl protective group. Within subclass (B),preferred compounds are those in which Y' is C₁ -C₇ alkyl and/or whereinD is the residue of an amino acid (especially a naturally occurringamino acid) or of a peptide containing 2 to 20 amino acid segments,especially an enkephalin, endorphin or LHRH analogue. Specific preferredcompounds of subclass (B) are those wherein D is a protected residue ofa natural amino acid, such as tryptophan or tyrosine, or other aminoacid/neurotransmitter such as GABA, γ-vinyl GABA or γ-acetylenic GABA;an antibiotic, e.g. a penicillin-type antibiotic, such as ampicillin,6-aminopenicillanic acid or amoxicillin, or a cephalosporin-typeantibiotic, such as cephalexin, ceforanide or cefroxadine; ananticancer/antitumor agent, e.g. a nitrogen mustard type such asmelphalan, a urea type such as DON, or other anticancer/antitumor agentsuch as acivicin or L-alanosine; a peptide such as met⁵ -enkephalin,leu⁵ -enkephalin, γ-endorphin, α-endorphin, β-endorphin, or anendorphin, enkephalin or LHRH analogue containing a COOH group and aprimary, secondary or tertiary amino group; a hypotensive, e.g.methyldopa; or a sympathetic stimulant, e.g. levodopa.

(C) Compounds of formulas (I) and (II) wherein the centrally actingamine from which D can be considered to be derived also contains atleast one --OH functional group, and D in formula (I) or (II) contains,in place of at least one of the --OH functional groups in said amine, atleast one --OY group wherein Y is a hydrolytically or metabolicallycleavable hydroxyl protective group. Within subclass (C), preferredcompounds are those wherein Y is an acyl group or a carbonate groupand/or wherein D is the residue of a neurotransmitter, especially acatecholamine, or LHRH or an analogue thereof. At the present time,preferred compounds in this general class include those in which D is aprotected residue of a neurotransmitter, especially a catecholamine suchas dopamine, epinephrine or norepinephrine, or other neurotransmittersuch as serotonin; of a structurally related compound such asphenylephrine or tyramine; or of LHRH or an LHRH analogue containing atyrosine, serine or threonine amino acid residue (i.e., an OH-containingportion) and a primary, secondary or tertiary amino group.

(D) Compounds of formulas (I) and (II) wherein the centrally actingamine from which D can be considered to be derived also contains atleast one --OH functional group and at least one --COOH functionalgroup, and D in formula (I) or (II) contains, in place of at least oneof the --OH functional groups and at least one of the --COOH functionalgroups in said amine, at least one --OY group and at least one --COOY'group, respectively, wherein Y is a hydrolytically or metabolicallycleavable hydroxyl protective group and Y' is a hydrolytically ormetabolically cleavable carboxyl protective group. Within subclass (D),preferred compounds are those wherein Y is an acyl group or a carbonategroup and/or Y' is C₁ -C₇ alkyl. Of particular interest are thecompounds in which D is a protected residue of a hypotensive, e.g.methyldopa; a sympathetic stimulant, e.g. levodopa; a hydroxy-containingamino acid, e.g. threonine, tyrosine or serine, or a peptide containingsuch an amino acid, e.g. leu⁵ -enkephalin, met⁵ -enkephalin,γ-endorphin, β-endorphin, α-endorphin, other enkephalin or endorphin, oran analogue of LHRH containing a COOH group, a primary, secondary ortertiary amino function and a hydroxy-containing amino acid. Preferredpeptides contain 2 to 20 amino acid segments.

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims.

What is claimed is:
 1. A compound of the formula ##STR646## or anon-toxic pharmaceutically acceptable salt thereof, wherein D is theresidue of doxorubicin or daunorubicin, said residue having the formula##STR647## and ##STR648## is a radical of the formula ##STR649## whereinthe dotted line in formula (a) indicates the presence of a double bondin either the 4 or 5 position of the dihydropyridine ring; the dottedline in formula (b) indicates the presence of a double bond in eitherthe 2 or 3 position of the dihydroquinoline ring system; m is zero orone; n is zero, one or two; p is zero, one or two, provided that when pis one or two, each R in formula (b) can be located on either of the twofused rings; q is zero, one or two, provided that when q is one or two,each R in formula (c) can be located on either of the two fused rings;and each R is independently selected from the group consisting of halo,C₁ -C₇ alkyl, C₁ -C₇ alkoxy, C₂ -C₈ alkoxycarbonyl, C₂ -C₈ alkanoyloxy,C₁ -C₇ haloalkyl, C₁ -C₇ alkylthio, C₁ -C₇ alkylsulfinyl, C₁ -C₇alkylsulfonyl, --CH═NOR'" wherein R'" is H or C₁ -C₇ alkyl, and--CONR'R" wherein R' and R", which can be the same or different, areeach H or C₁ -C₇ alkyl.
 2. A compound according to claim 1, wherein n,m, p or q is one, and wherein R is located in the 3 position of thedihydropyridine ring, in the 3 position of the dihydroquinoline ringsystem or in the 4 position of the dihydroisoquinoline ring system.
 3. Acompound according to claim 2, wherein R is --CONH₂.
 4. A compoundaccording to claim 1, wherein ##STR650## is a radical of the formula##STR651## wherein the dotted line indicates the presence of a doublebond in either the 4 or 5 position of the dihydropyridine ring; n iszero, one or two; and each R is independently selected from the groupconsisting of halo, C₁ -C₇ alkyl, C₁ -C₇ alkoxy, C₂ -C₈ alkoxycarbonyl,C₂ -C₈ alkanoyloxy, C₁ -C₇ haloalkyl, C₁ -C₇ alkythio, C₁ --,alkylsulfinyl, C₁ -C₇ alkylsulfonyl, --CH═NOR'" wherein R'" is H or C₁-C₇ alkyl, and --CONR'R" wherein R' and R", which can be the same ordifferent, are each H or C₁ -C₇ alkyl.
 5. A compound according to claim4, wherein n is one and R is located in the 3 position of thedihydropyridine ring.
 6. A compound according to claim 5, wherein R is--CONH₂.
 7. A compound according to claim 6, having the formula##STR652##
 8. A non-toxic pharmaceutically acceptable quaternary salthaving the formula ##STR653## wherein D is the residue of doxorubicin ordaunorubicin, said residue having the formula ##STR654## respectively,X⁻ is the anion of a non-toxic pharmaceutically acceptable acid and##STR655## is a radical of the formula ##STR656## wherein n is zero, oneor two; p is zero, one or two, provided that when p is one or two, eachR in formula (b) can be located on either of the two fused rings; q iszero, one or two, provided that when q is one or two, each R in formula(c) can be located on either of the two fused rings; and each R isindependently selected from the group consisting of halo, C₁ -C₇ alkyl,C₁ -C₇ alkoxy, C₂ -C₈ alkoxycarbonyl, C₂ -C₈ alkanoyloxy, C₁ -C₇haloalkyl, C₁ -C₇ alkylthio, C₁ -C₇ alkylsulfinyl, C₁ -C₇ alkylsulfonyl,--CH═NOR'" wherein R'" is H or C₁ -C₇ alkyl, and --CONR'R" wherein R'and R", which can be the same or different, are each H or C₁ -C₇ alkyl.9. A pharmaceutical composition of matter comprising an effectiveantitumor or anticancer amount of a compound as claimed in claim 1 and anon-toxic pharmaceutically acceptable carrier therefor.
 10. Apharmaceutical composition according to claim 9, said composition beingformulated as a pharmaceutically acceptable sustained releasecomposition.